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Therefore, we hypothesized that <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2B6 variants would be associated with altered nicotine oxidation, and that nicotine metabolism by <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2B6 would be detected in human brain microsomes. We generated recombinant enzymes in insect cells corresponding to nine common <jats:italic><jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2B6<\/jats:italic> haplotypes and demonstrate genetically determined differences in nicotine oxidation to nicotine iminium ion and nornicotine for both (S) and (R)\u2010nicotine. Notably, the <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2B6.6 and <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2B6.9 variants demonstrated lower intrinsic clearance relative to the reference enzyme, <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2B6.1. In the presence of human brain microsomes, along with nicotine\u2010<jats:italic>N<\/jats:italic>\u2010oxidation, we also detect nicotine oxidation to nicotine iminium ion. However, unlike <jats:italic>N<\/jats:italic>\u2010oxidation, this activity is <jats:styled-content style=\"fixed-case\">NADPH<\/jats:styled-content> independent, does not follow Michaelis\u2010Menten kinetics, and is not inhibited by <jats:styled-content style=\"fixed-case\">NADP<\/jats:styled-content> or carbon monoxide. Furthermore, metabolism of common <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2B6 probe substrates, methadone and ketamine, is not detected in the presence of brain microsomes. We conclude that <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2B6 metabolizes nicotine stereoselectively and common <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2B6 variants differ in nicotine metabolism activity, but did not find evidence of <jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>2B6 activity in human brain.<\/jats:p>","DOI":"10.1002\/prp2.468","type":"journal-article","created":{"date-parts":[[2019,3,12]],"date-time":"2019-03-12T04:14:24Z","timestamp":1552364064000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Nicotine oxidation by genetic variants of <scp>CYP<\/scp>2B6 and in human brain microsomes"],"prefix":"10.1002","volume":"7","author":[{"given":"Adam Joseph","family":"Bloom","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Anesthesiology Washington University St. Louis Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan\u2010Fen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Duke University School of Medicine Durham North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan D.","family":"Kharasch","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Duke University School of Medicine Durham North 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